The concept of controlled, extended, or modified release of biologically active ingredients is well known, and can be very advantageous in the administering of said active ingredients. For example, in the area of pharmaceuticals, by extending the release of a pharmaceutically active ingredient it is possible to increase the time during which the blood plasma concentration of said active ingredient is between an upper limit, defined by the toxicological properties of said active ingredient and a lower limit defined by the efficacy of the said active ingredient. Particularly desirable are constant release rate and delayed release. Additionally, in the area of water treatment chemicals, controlled release can result in the more efficient use of the active ingredient because similar limits exist where the upper limit is defined by processing requirements, such as limiting corrosion and reducing toxicity to non-targeted organisms, and the lower limit is defined by efficacy. Further in the area of agricultural chemicals, controlled release is beneficial because similar limits exist where the upper limit is defined by pollution of the environment, and toxicity to non-targeted organisms, and the lower limit is defined by efficacy.
There are many examples of different methods known in the industry for modifying the release rate of active ingredients, including many commercialized formulations. One of the methods that has been used in the pharmaceutical art is to convert the drug active ingredient into a complex with an ion exchange resin to form a resinate. Resinates are salts formed between ion exchange resins and ionizable active ingredients. Cation exchange resins form resinates with basic active ingredients. Anion exchange resins form resinates with acidic active ingredients. In the resinate the active ingredient and the resin are in their ionized forms. When resinates are exposed to fluids such as physiological fluids the active ingredient can be released from the resinate by the mechanism of ion exchange. The rate of release of active ingredients from resinates depends on several factors which are well known in the industry. These include, but are not limited to, degree of cross-linking of the ion exchange resin, the particle size of the resinate, the pK of the functional groups of the resin, the solubility of the active ingredient in the release fluid, the ionic strength and pH of the release fluid, the pK of the active ingredient, the molecular weight of the active ingredient, and the temperature. Coating the resin with a permeable membrane can also change the rate of release. Coating the resin with non-permeable membranes can change the conditions under which the release takes place depending on the conditions under which the membrane dissolves.
Using the variables described above, the resinate can be used to provide some control of the release rate, providing an extended release of the active ingredient. Because of the nature of the mechanism, resinates give a fast release to start, when the concentration of the active ingredient in the resinate is high, followed by a gradually reducing release rate as the concentration of active ingredient decreases. Because of this it has been a problem in the art of ion exchange resinate technology to achieve constant release or delayed release. Thus, the application of ion exchange resinate technology as a means of delivering active ingredients has been limited.
The art has attempted to achieve constant release rates and delayed release without the use of ion exchange resins. The osmotic pump (D. G. Pope et al, Journal of Pharmaceutical Sciences, Volume 74, pages 1108–1110. F Theeuwes et al, Journal of Pharmaceutical Sciences, Volume 72, pages 253–258) achieves this by using osmotic pressure to eject the active substance from the device at a constant rate. This method can also be used to achieve delayed release. Another method used is the erodable tablet (U.S. Pat. No. 4,525,345. C. Kim et al, European Journal of Pharmaceutical Sciences Volume 7, pages 237–242) where the rate of erosion of the tablet is used to control the rate of release of the active substance. This method can also be used to achieve delayed release. A third method is the use of swellable polymeric matrices (G. Zao et al, Journal of Chinese Pharmaceutical Science, Volume 9, pages 104–107. U. Conte et al, S. T. P. Pharma Sci, Volume 4, pages 107–110) where the rate of swelling and diffusion control the rate of release. However, these methods are not applicable to all active ingredients or applications.
Thus, there is a need for alternative methods for controlling the release rates of active ingredients. Applicants have surprisingly discovered resinate/unloaded resin compositions for delivering active ingredients, exhibiting constant release rate and delayed release profiles. Thus, Applicants' invention solves the problems in the resinate art.
The following terms have the following meanings herein:
The term “release rate profile”, as used herein, means the rate at which the substance that is loaded on the resin appears in solution in the release medium. This can be expressed in terms of the instantaneous concentration of the substance in solution as a function of time, or expressed in terms of the percentage of total substance available that has appeared in solution in the release medium as a function of time.
The term “release medium” and as used herein, means the liquid medium into which the substances is being released. Examples of release media can be water, simulated intestinal fluid, simulated gastric fluid, simulated saliva, or the authentic physiological versions of these fluids, water, and various buffer solutions.
The term “ion exchange resin”, as used herein, means any insoluble polymer that can act as an ion exchanger.
The term “release”, as used herein, means the transfer of substance from the resinate into the release medium. When applied to a resin or resinate, the term “absorption”, as used herein, means the reverse of release, namely the transfer of substance from the medium into the ion exchange resin or resinate.
The term “water retention capacity” as used herein is used to describe the maximum amount of water that an ion exchange resin can retain within the polymer phase and in any pores. (ASTM D2187: Standard Test Methods for Physical and Chemical Properties of Particulate Ion Exchange Resin. Test Method B: Water Retention Capacity)
The term “resinate,” as used herein, means a complex formed between an active ingredient and an ion exchange resin. It is also known as a loaded resin. The term “resinate” can also be expressed as an active ingredient/ion exchange resin complex.
Further, ion exchange resins are characterized by their capacity to exchange ions. This is expressed as the “Ion Exchange Capacity.” For cation exchange resins the term used is “Cation Exchange Capacity,” and for anion exchange resins the term used is “Anion Exchange Capacity.” The ion exchange capacity is measured as the number equivalents of an ion that can be exchanged and can be expressed with reference to the mass of the polymer (herein abbreviated to “Weight Capacity”) or its volume (often abbreviated to “Volume Capacity”). A frequently used unit for weight capacity is “milliequivalents of exchange capacity per gram of dry polymer.” This is commonly abbreviated to “meq/g.”
Ion exchange resins are manufactured in different forms. These forms can include spherical and non-spherical particles with size in the range of 0.00001 mm to 2 mm. The non-spherical particles are frequently manufactured by grinding of the spherical particles. Products made in this way typically have particle size in the range 0.0001 mm to 0.2 mm. The spherical particles are frequently known in the art as ‘Whole Bead.’ The non-spherical particles are frequently known in the art as ‘Powders.’